Insulin-like growth factor-l (IGF-I) is essential to normal brain growth. It has been shown to exert actions on neural stem cells (NSC) and each major neural cell lineage (neurons, oligodendrocytes, and astrocytes). We have demonstrated that IGF-I increases neuron number by stimulating progenitor proliferation early in neurogenesis and later by inhibiting neuron apoptosis. IGF-I also stimulates neuritic outgrowth and synaptogenesis. Furthermore we, and others, have provided compelling evidence that IGF-I stimulates oligodendrocyte development and myelination, and other evidence suggests that IGF-I instructs NSC to commit to the oligodendrocyte lineage. This data raises the question of how IGF-I can elicit such a wide variety of responses. This proposal is based on the concept that in vivo IGF-I responses are dependent upon context. We will test the following working hypotheses: 1) IGF-I stimulates the proliferation of NSC and fate-committed precursors of each neural lineage;2) IGF-I does not determine lineage fate;and 3) IGF-I is a major stimulator of neuron progenitor (NP) proliferation throughout life, exerting marked effects on neurogenesis and following injury. Our studies will focus on the developing dentate gyrus (DG) because it retains NSC and the capacity to generate new neural cells throughout life. We will address 3 specific aims: I. To understand the context of IGF-I actions, we will use laser capture microdissection and rtPCR to define the precise cells that express the IGFs, the type 1 receptor (IGF1R) and IGF binding proteins (IGFBP) during normal mouse DG development and following neonatal hypoxic/ischemic injury;II. Using mutant mice with altered IGF-I expression (IGF-I nulls and mice that overexpress IGF-I from early in neural development) or action (mice with ablated IGF1R expression in NP), we will investigate IGF-I effects on DG NSC proliferation, NSC fate, and neurogenesis during development;and III. Determine the consequences of neonatal ischemia/hypoxia on DG neurogenesis in normal and IGF-I and IGF1R mutant mice.